Role of Estrogen Receptors in Lung Function

哮喘是一种呼吸道慢性疾病。尽管改善了治疗方案，但在发达国家，哮喘的患病率和严重程度似乎在增加。这种疾病的临床特征是气道阻塞和气道对各种刺激的高反应性，如甲胆碱（一种胆碱能激动剂，通过刺激自主神经系统的副交感神经臂引起支气管收缩），组织学上表现为气道炎症和水肿，支气管平滑肌肥大和粘液腺增生。哮喘与过敏性疾病有关，大量证据表明，在室内环境中暴露于过敏原会影响哮喘的发展、持续和严重程度。最近的研究也表明，吸入细菌成分如LPS可引起急慢性气流阻塞、气道炎症和气道重塑。最近几项研究的证据表明性激素在改变肺功能和哮喘发病机制中的作用。我们对两项大型全国性调查数据的分析表明，在青春期后和绝经前，女性患哮喘的比例高于男性。据报道，在月经前和月经期间肺功能下降和哮喘症状恶化。怀孕期间哮喘症状的改善已得到证实。口服避孕药和激素替代疗法与改善肺功能和减少哮喘加重有关。在过去30年中，哮喘患病率的上升与口服避孕药的使用增加以及与具有雌激素和雄激素作用的环境化学物质的接触增加相一致。虽然这些研究表明性激素、肺功能和人类哮喘之间存在复杂的关系，但这些关联背后的机制仍未得到研究。雌激素通过α或β er介导转录和非基因组效应。这两种受体都在肺中表达，但它们在肺中的功能在很大程度上是未知的。使用基因靶向策略培养缺乏α - er （aERKO）或β - er （bERKO）的小鼠。先前对这些小鼠的研究已经将各种肺外器官的许多功能归因于这两种er中的一种或两种。重要的是，没有研究检查这些小鼠在基础条件下或环境相关刺激后的肺表型。因此，这两种er在肺中的功能作用仍未被发现。我们发现雌激素受体α敲除小鼠表现出多种肺功能异常，并且在基础条件下气道对吸入甲基胆碱的反应性增强。这与肺中M2毒蕈碱受体表达和功能降低有关。缺乏雌激素受体α也会导致气道反应性增加，而不会增加过敏原致敏和挑战后的炎症。这些数据表明雌激素受体- α是呼吸的重要调节因子，为解释性激素调节气道反应性提供了新的机制，并为哮喘和慢性阻塞性肺疾病的治疗提供了新的靶点

Asthma is a chronic disease of the airways. Despite improved treatment regimens, asthma prevalence and severity appear to be increasing in developed countries. This disease is characterized clinically by airway obstruction and airway hyperresponsiveness to a variety of stimuli such as methacholine (a cholinergic agonist that causes bronchoconstriction by stimulating the parasympathetic arm of the autonomic nervous system), and histologically by airway inflammation and edema, bronchial smooth muscle hypertrophy and mucus gland hyperplasia. Asthma is associated with allergic conditions and substantial evidence suggests that exposure to allergens in the indoor environment affects the development, persistence and severity of asthma. Recent studies also demonstrate that inhalation of bacterial components such as LPS can cause acute and chronic airflow obstruction, airway inflammation, and airway remodeling. Evidence from several recent studies suggests a role for sex hormones in modifying lung function and in the pathogenesis of asthma. Our analysis of data from two large national surveys indicates a higher prevalence of asthma among women compared to men after puberty and before menapause. Reduction in pulmonary function and worsening of asthma symptoms before and during menses has been reported. Improvements in asthma symptoms during pregnancy have been demonstrated. Oral contraceptives and hormone replacement therapy are associated with improved pulmonary function and decreased asthma exacerbation. The rise in asthma prevalence rates in the last 30 years coincides with the increased use of oral contraceptives and increased exposure to environmental chemicals with estrogenic and androgenic actions. While these studies suggest a complex relationship between sex hormones, lung function and asthma in humans, the mechanisms underlying these associations remain uninvestigated. Estrogens mediate both transcriptional and non-genomic effects via alpha or beta ERs. Both receptors are expressed in the lung but their functions in this organ are largely unknown. Mice lacking either the alpha-ER (aERKO) or the beta-ER (bERKO) were developed using gene targeting strategies. Previous studies with these mice have ascribed numerous functions in various extrapulmonary organs to either or both of the two ERs. Importantly, no studies have examined the lung phenotype of these mice under basal conditions or after environmentally relevant stimuli. Consequently the functional roles of the two ERs in the lung remains undiscovered. We found that estrogen receptor-alpha knockout mice exhibit a variety of lung function abnormalities and have enhanced airway responsiveness to inhaled methacholine under basal conditions. This is associated with reduced M2 muscarinic receptor expression and function in the lungs. Absence of estrogen receptor-alpha also leads to increased airway responsiveness without increased inflammation following allergen sensitization and challenge. These data suggest that the estrogen receptor-alpha is a critical regulator of respiration, provide a novel mechanism to explain sex hormone modulation of airway responsiveness, and identify a new therapeutic target for asthma and chronic obstructive pulmonary disease